The therapeutic effect and mechanism of parthenolide in skeletal disease, cancers, and cytokine storm.

Parthenolide (PTL or PAR) was first isolated from Magnolia grandiflora and identified as a small molecule cancer inhibitor. PTL has the chemical structure of C15H20O3 with characteristics of sesquiterpene lactones and exhibits the biological property of inhibiting DNA biosynthesis of cancer cells. In this review, we summarise the recent research progress of medicinal PTL, including the therapeutic effects on skeletal diseases, cancers, and inflammation-induced cytokine storm. Mechanistic investigations reveal that PTL predominantly inhibits NF-κB activation and other signalling pathways, such as reactive oxygen species. As an inhibitor of NF-κB, PTL appears to inhibit several cytokines, including RANKL, TNF-α, IL-1ß, together with LPS induced activation of NF-κB and NF-κB -mediated specific gene expression such as IL-1ß, TNF-α, COX-2, iNOS, IL-8, MCP-1, RANTES, ICAM-1, VCAM-1. It is also proposed that PTL could inhibit cytokine storms or hypercytokinemia triggered by COVID-19 via blocking the activation of NF-κB signalling. Understanding the pharmacologic properties of PTL will assist us in developing its therapeutic application for medical conditions, including arthritis, osteolysis, periodontal disease, cancers, and COVID-19-related disease.

Galanin family peptides: Molecular structure, expression and roles in the neuroendocrine axis and in the spinal cord.

Galanin is a neurohormone as well as a neurotransmitter and plays versatile physiological roles for the neuroendocrine axis, such as regulating food intake, insulin level and somatostatin release. It is expressed in the central nervous system, including hypothalamus, pituitary, and the spinal cord, and colocalises with other neuronal peptides within neurons. Structural analyses reveal that the human galanin precursor is 104 amino acid (aa) residues in length, consisting of a mature galanin peptide (aa 33-62), and galanin message-associated peptide (GMAP; aa 63-104) at the C-terminus. GMAP appears to exhibit distinctive biological effects on anti-fungal activity and the spinal flexor reflex. Galanin-like peptide (GALP) has a similar structure to galanin and acts as a hypothalamic neuropeptide to mediate metabolism and reproduction, food intake, and body weight. Alarin, a differentially spliced variant of GALP, is specifically involved in vasoactive effect in the skin and ganglionic differentiation in neuroblastic tumors. Dysregulation of galanin, GALP and alarin has been implicated in various neuroendocrine conditions such as nociception, Alzheimer's disease, seizures, eating disorders, alcoholism, diabetes, and spinal cord conditions. Further delineation of the common and distinctive effects and mechanisms of various types of galanin family proteins could facilitate the design of therapeutic approaches for neuroendocrine diseases and spinal cord injury.

The versatile roles of odontogenic ameloblast-associated protein in odontogenesis, junctional epithelium regeneration and periodontal disease.

Junctional epithelium (JE) is a vital epithelial component which forms an attachment to the tooth surface at the gingival sulcus by the adhesion of protein complexes from its basal layer. Disruption of the JE is associated with the development of gingivitis, periodontal disease, and alveolar bone loss. Odontogenic ameloblast-associated (ODAM) is comprised of a signal peptide and an ODAM protein with 12 putative glycosylation sites. It is expressed during odontogenesis by maturation stage ameloblasts and is incorporated into the enamel matrix during the formation of outer and surface layer enamel. ODAM, as a secreted protein which is accumulated at the interface between basal lamina and enamel, mediates the adhesion of the JE to the tooth surface; and is involved with extracellular signalling of WNT and ARHGEF5-RhoA, as well as intracellular signalling of BMP-2-BMPR-IB-ODAM. ODAM is also found to be highly expressed in salivary glands and appears to have implications for the regulation of formation, repair, and regeneration of the JE. Bioinformatics and research data have identified the anti-cancer properties of ODAM, indicating its potential both as a prognostic biomarker and therapeutic target. Understanding the biology of ODAM will help to design therapeutic strategies for periodontal and dental disorders.